title: Anti-aquaporin-1 autoantibodies in patients with neuromyelitis optica spectrum disorders.
abstract: Autoantibodies against aquaporin-4 (AQP4), a water channel in CNS astrocytes, are detected in ∼50-80% of patients with neuromyelitis optica spectrum disorders (NMOsd), characterized by longitudinally extensive transverse myelitis (LETM) and/or optic neuritis. Although these autoantibodies present an invaluable biomarker for NMOsd and for the differential diagnosis of multiple sclerosis (MS), diagnosis of anti-AQP4-seronegative NMOsd remains challenging. We hypothesized that seronegative NMOsd patients might have autoantibodies against aquaporin-1 (AQP1), another water channel in CNS astrocytes. We initially developed a radioimmunoprecipitation assay to search for anti-AQP1 antibodies in sera from 632 individuals. Anti-AQP1 or anti-AQP4 autoantibodies were detected in 16.7% and 12%, respectively, of 348 patients with suspected NMOsd. Anti-AQP1 specificity was confirmed by competition, protein immunoblotting and ELISA assays, whereas epitope localization was studied by immunoadsorption on intact cells expressing AQP1 and peptide mapping experiments. Most anti-AQP1 autoantibodies were of the complement-activating IgG1 subclass and the majority bound to the extracellular domain of AQP1, suggesting a possible pathogenic role. Five out of 42 MS patients had anti-AQP1 antibodies, but 2 of them also had spinal cord lesions, while the anti-AQP1 antibodies in the other 3 bound to the cytoplasmic domain of AQP1. Anti-AQP1 antibodies were not detected in 100 healthy individuals or 142 patients with non-demyelinating neuroimmune diseases. Analysis of 17 anti-AQP1+/anti-AQP4- patients with suspected NMOsd showed that 5 had NMO and 11 had LETM. 12/17 of these sera bound predominantly to the extracellular AQP1 loop-Α. Overall, we found that anti-AQP1 autoantibodies are present in a subgroup of patients with chronic demyelination in the CNS and similarities with anti-AQP4-seronegative NMOsd, offering a novel potential biomarker for CNS demyelination disorders.
authors.affiliation: Department of Biochemistry, Hellenic Pasteur Institute, Athens, Greece ; Department of Neurology, General Hospital "Red Cross", Athens, Greece.
authors.forename: John S
authors.initials: JS
authors.lastname: Tzartos
authors.forename: Christos
authors.initials: C
authors.lastname: Stergiou
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kilidireas
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Zisimopoulou
authors.forename: Thomas
authors.initials: T
authors.lastname: Thomaidis
authors.forename: Socrates J
authors.initials: SJ
authors.lastname: Tzartos
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000918:Antibody Specificity / Q000276:immunology; D000941:Antigens / Q000276:immunology; D051398:Aquaporin 1 / Q000737:chemistry / Q000276:immunology*; D051401:Aquaporin 4 / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008099:Liver / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009471:Neuromyelitis Optica / Q000097:blood / Q000276:immunology*; D011485:Protein Binding; D011489:Protein Denaturation; D017434:Protein Structure, Tertiary; D055815:Young Adult
chemical_list: C496020:AQP1 protein, human; C496030:AQP4 protein, human; D000941:Antigens; D051401:Aquaporin 4; D001323:Autoantibodies; D007074:Immunoglobulin G; D051398:Aquaporin 1